Insulin and Oral Hypoglycemic Agents · 2020. 1. 22. · Insulin and Insulin Analogs •Insulin [IN-su-lin] is a polypeptide hormone consisting of two peptide chains that are connected

Insulin and Oral

Hypoglycemic Agents

Diabetes Mellitus

Summary of Drugs Used in the Treatment of Diabetes

Diabetes Treatment • A person with type 1 diabetes must rely on

exogenous insulin to control hyperglycemia,

avoid ketoacidosis, and maintain acceptable

levels of glycosylated hemoglobin (HbA1c).

• The goal of insulin therapy in type 1 diabetes

is to maintain blood glucose as close to

normal as possible and to avoid wide swings

in glucose.

• The use of home blood glucose monitors

facilitates frequent self-monitoring and

treatment with insulin.

Diabetes Treatment • The goal in treating type 2 diabetes is to maintain

blood glucose within normal limits and to prevent

the development of long-term complications.

Weight reduction, exercise, and dietary modification

decrease insulin resistance and correct hyperglycemia

in some patients with type 2 diabetes.

Most patients require pharmacologic intervention with

oral glucose-lowering agents.

As the disease progresses, β-cell function declines

and insulin therapy is often needed to achieve

satisfactory glucose levels.

Insulin and Insulin Analogs

• Insulin [IN-su-lin] is a polypeptide hormone consisting of two peptide chains that are connected by disulfide bonds.

• It is synthesized as a precursor (proinsulin) that undergoes proteolytic cleavage to form insulin and C-peptide, both of which are secreted by the β cells of the pancreas.

• Insulin secretion is regulated by blood glucose levels, certain amino acids, other hormones, and autonomic mediators.

• Secretion is most often triggered by increased blood glucose, which is taken up by the glucose transporter into the β cells of the pancreas.

• There, it is phosphorylated by glucokinase, which acts as a glucose sensor.

• The products of glucose metabolism enter the mitochondrial respiratory chain and generate adenosine triphosphate (ATP).

• The rise in ATP levels causes a blockade of K+ channels, leading to membrane depolarization and an influx of Ca2+.

• The increase in intracellular Ca2+ causes pulsatile insulin exocytosis.

INSULIN AND INSULIN ANALOGS Mechanism of action

• Exogenous insulin is administered to replace absent insulin secretion in

type1 diabetes or to supplement insufficient insulin secretion in type 2

diabetes.

Pharmacokinetics and fate

• Human insulin is produced by recombinant DNA technology using strains

of Escherichia coli or yeast that are genetically altered to contain the gene

for human insulin.

• Modification of the amino acid sequence of human insulin produces insulins with different pharmacokinetic properties.

• Insulin preparations vary primarily in their onset and duration of activity.

• For example, insulin lispro, aspart, and glulisine have a faster onset and

shorter duration of action than regular insulin, because they do not aggregate or form complexes.

• Dose, injection site, blood supply, temperature, and physical activity can also

affect the onset and duration of various insulin preparations.

• Because insulin is a polypeptide, it is degraded in the

gastrointestinal tract if taken orally.

• Therefore, it is generally administered by subcutaneous

injection.

• [Note: In a hyperglycemic emergency, regular insulin is

administered intravenously (IV).]

• Continuous subcutaneous insulin infusion (also called the

insulin pump) is another method of insulin delivery.

• This method of administration may be more convenient for

some patients, eliminating multiple daily injections of insulin.

• The pump is programmed to deliver a basal rate of insulin.

• In addition, it allows the patient to deliver a bolus of insulin to

cover mealtime carbohydrate intake and compensate for high

blood glucose.

Adverse reactions to insulin • Hypoglycemia is the most serious and

common adverse reaction to insulin.

• Other adverse reactions include weight gain.

• local injection site reactions, and

lipodystrophy.

• Lipodystrophy can be minimized by rotation of

injection sites.

• Diabetics with renal insufficiency may require a

decrease in insulin dose.

Insulin preparations • Insulin preparations are

classified as

• Rapid.

• Short .

• Intermediate.

• Long-acting.

• It is important that

clinicians exercise caution

when adjusting insulin

treatment, paying strict

attention to the dose and

type of insulin.

Rapid-acting and short-acting insulin preparations

• Four preparations fall into this category:

Regular insulin.

Insulin lispro [lis-proe].

Insulin aspart [as-part].

Insulin glulisine [gloo-LYSEeen].

• Regular insulin is a short-acting, soluble, crystalline zinc

insulin.

• Insulin lispro, aspart, and glulisine are classified as rapid-

acting insulins.

• Modification of the amino acid sequence of regular insulin

produces analogs that are rapid-acting insulins.

• For example, insulin lispro differs from regular insulin in that the

lysine and proline at positions 28 and 29 in the B chain are

reversed

• This modification results in more rapid absorption,

a quicker onset, and a shorter duration of action

after subcutaneous injection.

• Peak levels of insulin lispro are seen at 30 to 90

minutes, as compared with 50 to 120 minutes for

regular insulin.

• Insulin aspart and insulin glulisine have

pharmacokinetic and pharmacodynamic properties

similar to those of insulin lispro.

• Rapid- or short-acting insulins are administered to

mimic the prandial (mealtime) release of insulin and

to control postprandial glucose.

• They may also be used in cases where swift

correction of elevated glucose is needed.

• Rapid- and short-acting insulins are usually used in

conjunction with a longer-acting basal insulin that

provides control of fasting glucose.

Regular insulin should be injected subcutaneously

30 minutes before a meal, whereas

Rapid-acting insulins are administered in the 15

minutes proceeding a meal or within 15 to 20

minutes after starting a meal.

• Rapid-acting insulins are commonly used in external

insulin pumps, and they are suitable for IV

administration, although regular insulin is most

commonly used when the IV route is needed.

Intermediate-acting insulin

• Neutral protamine Hagedorn (NPH) insulin is an

intermediate-acting insulin formed by the addition of zinc and

protamine to regular insulin.

• [Note: Another name for this preparation is insulin isophane.]

• The combination with protamine forms a complex that is less

soluble, resulting in delayed absorption and a longer duration

of action.

• NPH insulin is used for basal (fasting) control in type 1 or 2

diabetes and is usually given along with rapid- or short-acting

insulin for mealtime control.

• NPH insulin should be given only subcutaneously (never IV),

and it should not be used when rapid glucose lowering is

needed (for example, diabetic ketoacidosis).

Long-acting insulin preparations Insulin glargine [GLAR-geen] isoelectric point is lower than

that of human insulin, leading to formation of a precipitate at

the injection site that releases insulin over an extended period.

• It has a slower onset than NPH insulin and a flat, prolonged

hypoglycemic effect with no peak.

Insulin detemir [deh-TEE-meer] has a fatty acid side chain that

enhances association to albumin.

• Slow dissociation from albumin results in long-acting

properties similar to those of insulin glargine.

• As with NPH insulin, insulin glargine and insulin detemir are

used for basal control and should only be administered

subcutaneously.

• Neither long-acting insulin should be mixed in the same syringe

with other insulins, because doing so may alter the pharmacodynamic profile.

Insulin Combinations

• Various premixed combinations of human

insulins, such as 70% NPH insulin plus 30%

regular insulin, or 50% of each of these are also

available.

• Use of premixed combinations decreases the

number of daily injections but makes it more

difficult to adjust individual components of the

insulin regimen.

Standard Treatment Versus Intensive Treatment • Standard insulin therapy involves twice-daily

injections.

• Intensive treatment utilizes three or more injections

daily with frequent monitoring of blood glucose levels.

• The ADA recommends a target mean blood glucose

level of 154 mg/dL or less (HbA1c ≤ 7%), and intensive

treatment is more likely to achieve this goal.

• [Note: Normal mean blood glucose is approximately

115 mg/dL or less (HbA1c < 5.7%).]

• The frequency of hypoglycemic episodes, coma, and

seizures is higher with intensive insulin regimens .

• Patients on intensive therapy show a significant

reduction in microvascular complications of diabetes

such as retinopathy, nephropathy, and neuropathy

compared to patients receiving standard care.

• Intensive therapy should not be recommended for

patients with long-standing diabetes, significant

microvascular complications, advanced age, and those

with hypoglycemic unawareness.

• Intensive therapy has not been shown to significantly

reduce macrovascular complications of diabetes.

Examples of three regimens that provide both prandial and basal insulin replacement. B = breakfast; L = lunch; S = supper. NPH = neutral protamine Hagedorn

Synthetic Amylin Analog • Amylin is a hormone that is cosecreted with insulin from β cells

following food intake.

• It delays gastric emptying, decreases postprandial glucagon secretion, and

improves satiety.

• Pramlintide [PRAM-lin-tide] is a synthetic amylin analog that is indicated

as an adjunct to mealtime insulin therapy in patients with type 1 and type 2

diabetes.

• Pramlintide is administered by subcutaneous injection immediately prior

to meals.

• When pramlintide is initiated, the dose of mealtime insulin should be

decreased by 50% to avoid a risk of severe hypoglycemia.

• Other adverse effects include nausea, anorexia, and vomiting.

• Pramlintide may not be mixed in the same syringe with insulin, and it

should be avoided in patients with diabetic gastroparesis (delayed stomach

emptying), cresol hypersensitivity, or hypoglycemic unawareness.

Incretin Mimetics • Oral glucose results in a higher secretion of insulin

than occurs when an equal load of glucose is given

IV. This effect is referred to as the “incretin effect”

and is markedly reduced in type 2 diabetes.

• The incretin effect occurs because the gut releases

incretin hormones, notably glucagonlike peptide-1

(GLP-1) and glucose-dependent insulinotropic

polypeptidein response to a meal.

• Incretin hormones are responsible for 60% to 70% of

postprandial insulin secretion.

• Exenatide [EX-e-nah-tide] and liraglutide [LIR-a-

GLOO-tide] are injectable incretin mimetics used for

the treatment of type 2 diabetes.

Mechanism of action

• The incretin mimetics are analogs of GLP-1 that exert

their activity by acting as GLP-1 receptor agonists.

These agents improve glucose dependent insulin

secretion

Slow gastric emptying time

Reduce food intake by enhancing satiety (a feeling of

fullness)

Decrease postprandial glucagon secretion, and

promote β-cell proliferation.

Consequently, weight gain and postprandial

hyperglycemia are reduced, and HbA1c levels decline.

Pharmacokinetics and fate • Being polypeptides, exenatide and liraglutide must be

administered subcutaneously.

• Liraglutide is highly protein bound and has a long half-life,

allowing for once-daily dosing without regard to meals.

• Exenatide is eliminated mainly via glomerular filtration and

has a much shorter half-life.

• Because of the short duration of action, exenatide should be

injected twice daily within 60 minutes prior to morning and

evening meals.

• A once-weekly extended-release preparation is also

available.

• Exenatide should be avoided in patients with severe renal

impairment

Adverse effects

• The main adverse effects of the incretin mimetics

consist of nausea, vomiting, diarrhea, and

constipation.

• Exenatide and liraglutide have been associated with

pancreatitis.

• Patients should be advised to discontinue these agents

and contact their health care provider immediately if

they experience severe abdominal pain.

• Liraglutide causes thyroid C-cell tumors in rodents.

• It is unknown if it causes these tumors or thyroid

carcinoma in humans.

Oral Agents

• Oral agents are useful in the treatment of

patients who have type 2 diabetes that is not

controlled with diet.

• Patients who developed diabetes after age 40

and have had diabetes less than 5 years are

most likely to respond well to oral glucose-

lowering agents.

• Patients with long-standing disease may require

a combination of oral agents with or without

insulin to control hyperglycemia.

Sulfonylureas • These agents are classified as insulin secretagogues, because

they promote insulin release from the β cells of the pancreas.

• The sulfonylureas in current use are the second-generation

drugs glyburide [GLYE-byoor-ide], glipizide [GLIP-ih-zide], and

glimepiride [GLYE-me-pih-ride].

Mechanism of action: The main mechanism of action

includes

Stimulation of insulin release from the β cells of the pancreas.

Sulfonylureas block ATP-sensitive K+ channels, resulting in

depolarization, Ca2+ influx, and insulin exocytosis.

In addition, sulfonylureas may reduce hepatic glucose production and increase peripheral insulin sensitivity.

• Pharmacokinetics and fate: Given orally, these drugs bind to

serum proteins, are metabolized by the liver, and are

excreted in the urine and feces.

• The duration of action ranges from 12 to 24 hours.

• Adverse effects: Major adverse effects of the sulfonylureas are

weight gain, hyperinsulinemia, and hypoglycemia.

They should be used with caution in hepatic or renal

insufficiency, since accumulation of sulfonylureas may cause

hypoglycemia.

• Renal impairment is a particular problem for glyburide, as it

may increase the duration of action and increase the risk of

hypoglycemia significantly.

• Glipizide or glimepiride are safer options in renal dysfunction

and in elderly patients.

• Glyburide has minimal transfer across the placenta and may be

an alternative to insulin for diabetes in pregnancy.

Glinides

• This class of agents includes repaglinide [re-PAG-lin-ide] and nateglinide

[nuh-TAY-gli-nide]. Glinides are also considered insulin secretagogues.

Mechanism of action: Like the sulfonylureas, the glinides stimulate

insulin secretion.

• They bind to a distinct site on the β cell, closing ATP-sensitive K+ channels,

and initiating a series of reactions that results in the release of insulin.

• In contrast to the sulfonylureas, the glinides have a rapid onset and a short

duration of action. They are particularly effective in the early release of

insulin that occurs after a meal and are categorized as postprandial glucose

regulators.

Glinides should not be used in combination with sulfonylureas due to

overlapping mechanisms of action.

• This would increase the risk of serious hypoglycemia.

• Pharmacokinetics and fate: Glinides should be taken prior to a meal and

are well absorbed after oral administration. Both glinides are metabolized to inactive products by cytochrome P450 3A4 in the liver and are excreted

through the bile.

Adverse effects:

• Although glinides can cause hypoglycemia and

weight gain, the incidence is lower than that with

sulfonylureas.

• Drugs that inhibit CYP3A4, such as itraconazole,

fluconazole, erythromycin, and clarithromycin, may

enhance the glucose lowering effect of repaglinide.

• Drugs that induce CYP3A4, such as barbiturates,

carbamazepine, and rifampin, may have the opposite

effect.

• By inhibiting hepatic metabolism, the lipid-lowering

drug gemfibrozil may significantly increase the effects

of repaglinide, concurrent use is contraindicated.

• These agents should be used with caution in patients

with hepatic impairment.

Biguanides • Metformin [met-FOR-min], the only biguanide, is

classified as an insulin sensitizer.

• It increases glucose uptake and use by target

tissues, thereby decreasing insulin resistance.

• Unlike sulfonylureas, metformin does not promote

insulin secretion.

• Therefore, hyperinsulinemia is not a problem, and the

risk of hypoglycemia is far less than that with

sulfonylureas.

Biguanides Mechanism of action: The main mechanism of action of metformin

• Is reduction of hepatic gluconeogenesis. [Note: Excess glucose produced

by the liver is a major source of high blood glucose in type 2 diabetes,

accounting for high fasting blood glucose.]

• Metformin also slows intestinal absorption of sugars and improves

peripheral glucose uptake and utilization.

• Weight loss may occur because metformin causes loss of appetite.

• The ADA recommends metformin as the initial drug of choice for type 2

diabetes.

• Metformin may be used alone or in combination with other oral agents

or insulin.

• Hypoglycemia may occur when metformin is taken in combination with

insulin or insulin secretagogues, so adjustment in dosage may be required.

Pharmacokinetics and fate: Metformin is well

absorbed orally, is not bound to serum proteins, and

is not metabolized.

• Excretion is via the urine.

Adverse effects: These are largely gastrointestinal.

Metformin is contraindicated in renal dysfunction due

to the risk of lactic acidosis.

• Metformin should be used with caution in patients

older than 80 years and in those with heart failure or

alcohol abuse.

• Long-term use may interfere with vitamin B12

absorption.

Other uses: In addition to type 2

diabetes

• Metformin is effective in the treatment of

polycystic ovary syndrome.

• It lowers insulin resistance seen in this

disorder and can result in ovulation and,

therefore, possibly pregnancy.

Thiazolidinediones • The thiazolidinediones (TZDs) are also insulin

sensitizers. The two members of this class are

Pioglitazone [pye-oh-gli-ta-zone] and

Rosiglitazone [roe-si-GLIH-ta-zone].

• Although insulin is required for their action, the

TZDs do not promote its release from the β

cells, so hyperinsulinemia is not a risk.

Mechanism of action: The TZDs lower insulin

resistance by acting as agonists for the peroxisome

proliferator–activated receptor-γ (PPARγ), a nuclear

hormone receptor.

Activation of PPARγ regulates the transcription of

several insulin responsive genes, resulting in increased

insulin sensitivity in adipose tissue, liver, and skeletal

muscle.

Effects of these drugs on cholesterol levels are of

interest.

• Rosiglitazone increases LDL cholesterol and

triglycerides, whereas pioglitazone decreases

triglycerides.

• Both drugs increase HDL cholesterol.

• The TZDs can be used as monotherapy or in

combination with other glucose-lowering

agents or insulin.

• The dose of insulin may have to be lowered

when used in combination with these agents.

• The ADA recommends pioglitazone as a

second- or third-line agent for type 2 diabetes.

• Rosiglitazone is less utilized due to concerns

regarding cardiac adverse effects.

• Pharmacokinetics and fate: Pioglitazone and rosiglitazone are well absorbed after oral administration and are extensively

bound to serum albumin.

• Both undergo extensive metabolism by different CYP450

isozymes.

• Some metabolites of pioglitazone have activity.

• Renal elimination of pioglitazone is negligible, with the

majority of active drug and metabolites excreted in the bile and

eliminated in the feces.

• Metabolites of rosiglitazone are primarily excreted in the urine.

• No dosage adjustment is required in renal impairment.

• These agents should be avoided in nursing mothers.

• Adverse effects: A few cases of liver toxicity have

been reported with these drugs, and periodic

monitoring of liver function is recommended.

• Weight gain can occur because TZDs may increase

subcutaneous fat and cause fluid retention.

• [Note: Fluid retention can worsen heart failure. These

drugs should be avoided in patients with severe heart

failure.]

• TZDs have been associated with osteopenia and

increased fracture risk.

• Pioglitazone may also increase the risk of bladder

cancer.

• Several meta-analyses identified a potential increased

risk of myocardial infarction and death from

cardiovascular causes with rosiglitazone.

• As a result, use of rosiglitazone was limited to patients

enrolled in a special restricted access program.

• After a further review of safety data, the restrictions on

rosiglitazone use were subsequently lifted.

• Other uses: As with metformin, the relief of insulin

resistance with the TZDs can cause ovulation to

resume in premenopausal women with polycystic

ovary syndrome.

α-Glucosidase inhibitors

Acarbose [AY-car-bose] and miglitol [MIG-li-tol] are oral agents

used for the treatment of type 2 diabetes.

Mechanism of action: Located in the intestinal brush border, α-glucosidase enzymes break down carbohydrates into glucose and other

simple sugars that can be absorbed.

• Acarbose and miglitol reversibly inhibit α-glucosidase enzymes.

• When taken at the start of a meal, these drugs delay the digestion of

carbohydrates, resulting in lower postprandial glucose levels.

• Since they do not stimulate insulin release or increase insulin sensitivity,

these agents do not cause hypoglycemia when used as monotherapy.

• However, when used with insulin secretagogues or insulin, hypoglycemia

may develop. [Note: It is important that hypoglycemia in this context be

treated with glucose rather than sucrose, because sucrase is also inhibited by

these drugs.]

Pharmacokinetics and fate: Acarbose is poorly absorbed.

• It is metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine.

• Miglitol is very well absorbed but has no systemic effects.

• It is excreted unchanged by the kidney.

Adverse effects: The major side effects are flatulence, diarrhea, and abdominal cramping.

• Adverse effects limit the use of these agents in clinical practice.

• Patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use these drugs.

Dipeptidyl peptidase-4 inhibitors

• Alogliptin [al-oh-GLIP-tin], linagliptin [lin-a-GLIP-tin], saxagliptin [saxa- GLIP-tin],

and sitagliptin [si-ta-GLIP-tin] are orally active dipeptidyl peptidase-4 (DPP-4)

inhibitors used for the treatment of type 2 diabetes.

Mechanism of action: These drugs inhibit the enzyme DPP-4, which is responsible

for the inactivation of incretin hormones such as GLP-1.

• Prolonging the activity of incretin hormones increases insulin release in

response to meals and reduces inappropriate secretion of glucagon.

• DPP-4 inhibitors may be used as monotherapy or in combination with sulfonylureas,

metformin, TZDs, or insulin.

• Unlike incretin mimetics, these drugs do not cause satiety, or fullness, and are

weight neutral.

Pharmacokinetics and fate: The DPP-4 inhibitors are well absorbed after oral

administration.

• Food does not affect the extent of absorption.

• All DPP-4 inhibitors except linagliptin require dosage adjustments in renal

• dysfunction.

Adverse effects: In general, DPP-4 inhibitors are well tolerated, with the most

common adverse effects being nasopharyngitis and headache.

• Although infrequent, pancreatitis has occurred with use of all DPP-4 inhibitors.

Sodium–glucose cotransporter 2 inhibitors

Canagliflozin [kan-a-gli-floe-zin]

Dapagliflozin [dap-a-gli-floezin]

Mechanism of action: The sodium–glucose cotransporter 2

• (SGLT2) is responsible for reabsorbing filtered glucose in the tubular lumen of the

kidney. By inhibiting SGLT2, these agents decrease reabsorption of glucose, increase

urinary glucose excretion, and lower blood glucose.

• Inhibition of SGLT2 also decreases reabsorption of sodium and causes osmotic

diuresis. Therefore, SGLT2 inhibitors may reduce systolic blood pressure. However,

they are not indicated for the treatment of hypertension.

Pharmacokinetics and fate: These agents are given once daily in the morning.

• Canagliflozin should be taken before the first meal of the day.

• While the primary route of excretion for canagliflozin is via the feces, about one-third

of a dose is renally eliminated.

• hese agents should be avoided in patients with renal dysfunction.

Adverse effects: The most common adverse effects with SGLT2

• inhibitors are female genital mycotic infections (for example, vulvovaginal

candidiasis), urinary tract infections, and urinary frequency.

• Hypotension has also occurred, particularly in the elderly or patients on diuretics.

• Thus, volume status should be evaluated prior to starting these agents.

Other agents • Both the dopamine agonist

bromocriptine and the bile acid

sequestrant colesevelam produce modest reductions in HbA1c.

• The mechanism of action of glucose

lowering is unknown for both of these

drugs.

• Their modest efficacy and adverse effects

limit their use in clinical practice.